Various sulfoxide derivatives are known, and more particularly pyridinyl-methyl-sulfinyl benzimidazoles, useful in therapeutics as drugs presenting inhibiting properties of the proton pump, that is to say drugs which inhibit the secretion of gastric acid and are useful in the treatment of gastric and duodenal ulcers. The first known derivative of the series of proton pump inhibitors is omeprazole, or 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole described in patent EP 005.129, which possesses gastric acid secretion inhibiting properties, and is widely used as an anti-ulcerative in human therapeutics. Other derivatives of benzimidazole with similar structures are known by their generic names, for example rabeprazole, pantoprazole and lansoprazole, which all present a similar structure and can be related to the group of pyridinyl-methyl-sulfinyl-benzimidazoles.
Tenatoprazole, or 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]imidazo[4,5-b]pyridine, is described in patent EP 254.588. It is also one of the drugs considered as proton pump inhibitors and can generally be used in the treatment of gastro-oesophageal reflux disease, of digestive haemorrhages, and dyspepsia. However, tenatoprazole can be structurally differentiated from the other above-mentioned proton pump inhibitors in as much as it comprises an imidazo-pyridinyl nucleus instead of a benzimidazole nucleus.
All these compounds are sulfoxides presenting an asymmetry on the sulphur atom and can therefore be under the form of a racemic mixture of two enantiomers. It may be useful to separate them selectively under the form of one or the other of the two enantiomers with R and S configurations, or (+) and (−), whose specific properties can be sensibly different. Thus, patent application No WO 2004060891 describes the S enantiomer of tenatoprazole.
Various methods have been described in the scientific literature to prepare one or the other enantiomer of these sulfoxides in a selective or preponderant manner, in particular omeprazole and its enantiomer of S configuration, esomeprazole, as well as its salts such as sodium or magnesium salts.
Thus, patent EP 652.872 describes a method for the preparation of the magnesium salt of the (−) enantiomer of omeprazole via the ester comprising a chiral acyloxymethyl group, separation of the diastereo-isomers and solvolysis in an alkaline solution. U.S. Pat. No. 5,776,765 describes a method using the stereoselective bio-reduction of a racemic mixture of sulfoxide into the corresponding sulphide, using a micro-organism comprising a DMSO reductase, and allowing for a mixture to be obtained that is highly enriched in (−) enantiomer compared to the (+) enantiomer.
H. Kagan et al., have described an asymmetric oxidation system of sulphides into sulfoxides catalysed by a complex of titanium isopropoxide and optically active diethyl tartrate, using tert-butyl hydroperoxide as an oxidizing agent in the presence of water, at a temperature lower than 0° C. [see P. Pitchen and al. J. Am. Chem. Soc. 106, pp. 8188-93 (1984)]. S. Zhao, O, Samuel and H. Kagan, Tetrahedron vol. 43, pp. 5135-44 (1987) have demonstrated that the enantioselectivity could be improved using cumene hydroperoxide under the same reaction conditions. Various variations of the method of Kagan have been developed and for example, U.S. Pat. No. 5,948,789 concerns the enantioselective preparation of various sulfoxides, and more particularly of the (−) enantiomer of omeprazole or of its sodium salts, by oxidation of the corresponding sulphide (“prochiral” sulphide) by an oxidizing agent in a particular solvent such as toluene and ethyl acetate in the presence of a base, the reaction being catalysed by a titanium complex obtained from a titanium(IV) compound, preferably titanium isopropoxide, and a chiral ligand chosen among aliphatic and aromatic diols, notably L(−)- or D(−)-diethyl tartrate, in presence of water. The addition of a base to the reaction medium improves the enantioselectivity of the oxidation reaction of sulphide to sulfoxide. The method described in this patent allows for a mixture to be obtained that is enriched in one or the other of the (−) and (+) enantiomers, according to the ligand used.
The above-mentioned method of Kagan, as well as its variations, makes it possible to obtain sulfoxides with a structure of the benzimidazole type, such as omeprazole and its enantiomers, easily and in an enantioselective manner. However, in the case of sulfoxides of the imidazo-pyridinyl type, the low solubility of sulphides in usual solvents such as toluene generates a heterogeneous reaction medium accompanied by a loss of selectivity and an important formation of sulfone, in the range of 30%.
More particularly, some sulphides, in particular the prochiral sulphide of tenatoprazole, are slightly soluble in the usual solvents such as toluene and methylene chloride, and the choice of the solvent often raises difficulties. Thus, it is indicated in “Asymmetric Catalysis on Industrial Scale”, H. U. Blaser, E. Schmidt, 2004 Wiley-VCH Verlag GmbH & Co. KG, Grünstadt, ch. 7, p. 413, that aprotic and polar solvents have a negative influence on the asymmetric oxidation of sulphides with a pyridinyl-methyl-benzimidazole structure in catalytic systems such as those described above.
Therefore, a method able to produce sulfoxide enantiomers having an imidazole-pyridinyl structure, with a satisfactory enantiomeric excess, that would avoid the formation of sulfones, with good yield and purity conditions and being carried out in a solvent likely to be implemented on an industrial scale and presenting acceptable productivity levels, would be desirable.